It is well known that nicotine contained in cigarettes is deeply involved in habitual smoking. As a method for reducing smoking, administration of nicotine in a form other than smoking into the living organism has been proposed to suppress habitual smoking, and various nicotine administration methods have been proposed with the growing antismoking mood in the world. These methods are called what is called a nicotine supplement therapy, which includes the following methods.
One of them is a method of administering nicotine contained in a chewing gum or drug lozenge into the body from the mouth cavity. According to this administration method, in fact, a large amount of nicotine is swallowed down with the saliva, by which the nicotine is mostly metabolized and cleared from the blood during passage through the liver as in the case of oral administration of general drugs, and a high effect cannot be expected. Moreover, since this method is a temporary administration method, frequent application is necessary and, since nicotine directly touches the inner wall of the mouth and esophagus, uncomfortable side effects such as bad taste, heartburn, nausea, hiccup and the like are caused.
There is another method wherein a nicotine-containing solution is placed in a plastic one-time container or multiple-time use container, which is then inserted into a nostril for direct administration of the nicotine solution in the container through the nasal mucous membrane. However, this method is not preferable from a hygiene standpoint, since the container directly contacts the nasal mucous membrane. In addition, handling and management is difficult. Moreover, since only a temporary effect is expected as in the above method, frequent administration is necessary. In particular, this method is problematic since it includes insertion of the container into the nostril, which makes administration in front of others embarrassing, and the like.
In contrast to the above-mentioned two administration methods, various transdermal preparations have recently been developed, which aim at administering nicotine transdermally. Many patent applications directed to transdermal preparations have been filed, some of which have already been put to practice as preparations.
While general advantages of the transdermal preparation are already known widely, when applied to administration of nicotine, in particular, the preparation can resolve almost all the shortcomings of the above-mentioned two administration methods. The greatest merit of the preparation is considered to reside in the fact that the blood concentration can be maintained at a constant level for a long time after adhesion of the preparation, which decreases the trouble of administration.
However, the existing transdermal preparations of nicotine have the following problems.
For use of these nicotine transdermal preparations, a stop-smoking program has been set to quit smoking, and the program generally requires once-a-day adhesion for several weeks. The major side effects of this administration method include topical side effects such as itching, erythema and the like. To avoid skin irritation, therefore, package inserts of the preparations contain a written instruction to change the adhesion site every time of application. Furthermore, the skin irritation developed by peeling off of the preparation cannot be ignored, since the preparation needs to be exchanged every day. Accordingly, the development of a preparation causing less irritation has been desired.
As the adhesive currently used for the nicotine transdermal preparations, rubber adhesives represented by polyisobutylene (PIB) and styrene-isoprene-styrene block copolymer (SIS), and acrylic adhesives made of a copolymer of acrylic monomers can be mentioned. Of these, for PIB adhesive, a technique including mixing a high molecular weight component and a low molecular weight component to impart good adhesiveness to the human skin and cohesion (e.g., JP-B-3035346) is available. However, to achieve good skin adhesion, cohesion needs to be sacrificed somewhat and, when adhesiveness is preferentially considered, a problem occurs in that an adhesive flows out from the edge of a preparation during preservation due to the decreased cohesion, thus causing a cold flow (low temperature flow). The cold flow invites difficulty in taking out the preparation from the packaging material due to the attachment of adhesive in the packaging material. Particularly, since nicotine has a strong plasticizing action on the adhesive, the above-mentioned cold flow phenomenon remarkably expresses in a nicotine transdermal preparation. While normal rubber adhesives adhere well to the dry skin, since adhesives have low hydrophilicity, sweat is pooled in the interface between the skin and the adhesion surface during application, which may lift the adhesive and cause delamination, thus resulting in falling off during use. Furthermore, the sweat develops stuffiness to easily cause irritation, and a feeling during adhesion is not necessarily good.
On the other hand, a nicotine transdermal preparation containing an acrylic adhesive is associated with a problem of skin irritation caused by peeling off for exchange of the preparation. Moreover, since the preparation contains a non-woven fabric or paper inserted in its adhesive layer as an auxiliary material for applying liquid nicotine to the adhesive layer during production, the whole preparation is thick, physical irritation easily occurs during application due to the rough feeling of the preparation, and a feeling during adhesion is not necessarily good.
Nicotine is a highly volatile and highly toxic drug, where volatilization of nicotine has a risk of increasing the safety risk and the burden on the environment. Accordingly, various production methods of nicotine transdermal preparations in consideration of this point have been known.
JP-A-2002-531488 discloses a production method of a transdermal patch, which comprises using a hexane solvent having a low boiling point to prepare a coating solution for a silicone adhesive, and applying the solution at a low temperature to decrease the decomposition or loss of a liquid drug of nicotine and the like. While this method employs coating at a low temperature, it cannot completely eliminate the possibility of loss of nicotine, and may require charging of an increased amount and the like to achieve the desired amount of nicotine. In addition, since silicone adhesives are expensive, this method is disadvantageous from an economical aspect.
JP-A-11-502840 discloses a continuous production method of a pressure-sensitive skin adhesive sheet material containing a liquid, which comprises combining a coating medium containing the liquid and a polymer base layer, wherein nicotine is exemplified as a liquid drug to be contained. The liquid application in this case is characterized in that a polymer component is contained in the coating medium, where it is described that direct and uniform application of the nicotine liquid without processing was tried, namely, at 0% content of the polymer, but failed. The description suggests difficulty in applying nicotine as it is to an adhesive layer even by those of ordinary skill in the art.
JP-B-2708391 discloses a production method of a skin permeability administration tool comprising an absorption material such as a non-woven fabric impregnated with highly volatile nicotine, and adhesive layers sandwiching the substance. It is described that the main non-woven fabric layer to be used permits printing of nicotine, and does not function as a drug reservoir. According to this method, the preparation becomes thick due to the non-woven fabric sandwiched in the plaster, which may impair a soft feeling of the preparation and influence adhesion of the preparation. The preparation is economically disadvantageous in that the production cost becomes high.
JP-B-2763773 discloses a production method of a treating product, by introducing a depot containing an active substance such as nicotine and the like into a reservoir matrix of an adhesive and the like. In the example of this reference, the depot containing nicotine contains EUDRAGIT E 100. The depot is added to a non-woven fabric to give a plaster, where the non-woven fabric as an inactive auxiliary substance helps uniform dispersion of nicotine. This reference does not disclose a technique to apply nicotine without using an inactive auxiliary substance.
While various publications are known as regards nicotine transdermal preparations as mentioned above, they contain no disclosure relating to adhesive property and handling property.